Chronic myeloid leukemia (CML) is a hematopoetic stem cell disease with distinct biological and clinical features. In humans, a majority of CML (about 95%) has been found to be associated with a chromosomal abnormality that involves a t(9;22)(q34;q11) translocation, which results in the expression of the BCR/ABL fusion gene (Philadelphia Chromosome or Ph). The rest is associated with either a cryptic translocation that is invisible on G-banded chromosome preparations or a variant translocation involving another chromosome or chromosomes as well as chromosomes 9 and 22. CML usually presents in the so-called chronic phase, in which the clonal expansion of mature myeloid cells leads to an elevated white blood cell (WBC) count. Without curative intervention chronic phase CML will invariably transform through a phase of “acceleration,” often heralded by the appearance of increased immature myeloid cells in the bone marrow and peripheral blood, as well as new cytogenetic changes in addition to the Ph chromosome. Progression then proceeds quickly to blast crisis, with immature blast cells overwhelming the production of normal hematopoetic elements. Blast crisis is highly resistant to treatment, with death generally occurring from infection and bleeding complications secondary to the absence of normal granulocytes and platelets. The median time from diagnosis of chronic phase CML to progression blast crisis is approximately 3-4 years but the range of timing is quite broad, encompassing from 0.5-15 years (Faderl et al., 1999, Ann Intern Med 131:207).
There is a broad range of treatment options for CML. All treatments work far better on chronic phase disease than on accelerated or blast phase. The only known curative therapy for CML is stem cell transplantation, a complex and potentially toxic modality that carries a high potential for morbidity and mortality (Radich et al., 2003, Blood 102:31). Non-transplant therapy includes alpha interferon, which can produce a major reduction in the proportion of Ph positive cells and extend the natural history of the disease in approximately 10-20% of cases (Kantarjian et al., 1999, J Clin Oncol 17:284). The tyrosine kinase inhibitor, imatinib mesylate, suppresses the Ph to the point where it is undetectable by cytogenetic evaluation (“complete cytogenetic remission”) in >70% of newly diagnosed chronic phase CML cases (Druker et al., 2001, N Engl J Med 344:1031). The duration of such responses is unknown, as is potential for cure with imatinib. Resistance to imatinib occurs (especially in advanced phase disease) often accompanied by point mutations in the active area of imatinib binding in the abl gene (Shah et al., 2002, Cancer Cell 2:117). The natural history of such relapses is unknown, though some appear to have a speedy entry into advanced disease (Branford et al., 2003, Blood 102:276).
U.S. Patent Application Publication No. 2003/0104426 A1 discloses genetic markers whose expression correlates with progression of CML. Specifically, the patent application discloses sets of markers whose expression patterns can be used to differentiate chronic phase individuals from those in blast crisis, and methods of using these markers to distinguish these conditions. The patent application also discloses kits containing ready-to-use microarrays and computer data analysis software for carrying out the disclosed methods.
PRAME (Preferentially Expressed Antigen of Melanoma) was identified as a tumor antigen recognized by cytotoxic T-cells against a melanoma surface antigen (Matsushita et al., 2001, Br J Haematol 112:916, 2001; van Baren et al., 1998, Br J Haematol 102:1376). PRAME has been found to be overexpressed in over 25% of leukemia, and has been found to be induced by Bcr-Abl in CML cell lines (Watari et al., 2000, FEBS Lett 466:367). PRAME over-expression has been described as one of the few features that characterize the transient myeloproliferative syndrome of Down's syndrome from the progressive acute megakaryoblastic leukemia found in that disorder (McElwaine et al., 2004, Br J Haematol 125:729).
The genetic events that cause the progression of chronic phase to blast crisis CML are unknown (Calabretta et al., 2004, Blood 103:4010; Shet et al., 2002, Leukemia 16:1402). Numerous genetic abnormalities have been demonstrated, including chromosomal changes including a multiplication of the Ph, the disruption of TP53, the deletion of the p15/p16 tumor suppressor genes (the latter only in lymphoid blast crisis). However, none of these changes are particularly common. Genetic instability is apparent in the additional chromosomal changes that occur with progression, though standard assays of instability, such as alterations in minisatellite repeats, is relatively uncommon (Wada et al., 1994, Blood 83:3449; Mori et al., 1997, Leukemia 11:151). Unfortunately, clinical and molecular tests cannot predict where on the “clock” of progression an individual lies at the time of the initial diagnosis, and this makes it impossible to tailor therapy to the degree of risk that faces an individual CML patient. It is also not possible to identify the subset of patients who will benefit most from the variety of therapy options, such as interferon, imatinib, or transplantation. Thus, presently tailoring therapy to individual risk is difficult. There is therefore a need to identify genes whose levels of expression change during the evolution of the chronic phase to blast crisis. There is a need for methods that utilize measured expression levels of such genes to determine the phase and/or progression of CML in a patient. There is also a need for methods of treating CML by targeting such genes.
Discussion or citation of a reference herein shall not be construed as an admission that such reference is prior art to the present invention.